The focus of this project is to elucidate mechanisms involved in the repetitive use of drugs, the long-term effects of drugs and the biochemical mechanisms underlying chronic drug taking and drug seeking behavior. In a series of studies, we treated animals with cocaine in a long-term, but intermittent fashion. The pattern of administration was similar to that observed in animals self-administering cocaine. We utilized Lewis rats as they show a propensity for self administering cocaine compared to other strains. We found that, after 10 days of withdrawal, there was a significant decrease in dopamine transporter (a cocaine receptor) binding in the nucleus accumbens but not in the striatum. The decrease in transporter binding in the accumbens was long- lasting and still apparent by 60 days after withdrawal. Thus, there is a long-lasting change in dopamine transporter in limbic areas which appears during the withdrawal period and which is persistent. This type of biochemical phenomena could be related to long-term effects of drugs in human populations. In an effort to elucidate the mechanism of this down regulation of transporter, we carried out an in situ hybridization study in collaboration with Dr. George Uhl. We found a significant reduction in dopamine transporter MRNA in midbrain cell groups that project to the nucleus accumbens. Changes in MRNA were not found in cell groups projecting to the striatum. These data indicate that changes in gene expression can occur during drug withdrawal and also that regulation of the dopamine transporter can involve a change in gene expression. Taken together, we have carried out a series of successful studies in changes in the dopamine transporter during chronic drug administration and withdrawal.